Heart failure is a progressive disease with extremely poor prognosis. The failing heart is characterized by impaired cardiac muscle function and increased interstitial fibrosis. The mechanisms initiating the transition from stable hypertrophy to irreversible heart failure are unknown. Our purpose was to determine whether the functional impairment of the failing heart is associated with changes in levels of mRNA encoding proteins responsible contraction and relaxation, and whether the increased fibrosis in the failing heart is related to induction of genes encoding extracellular matrix components. We studied hearts of 18-24 mo spontaneously hypertensive rats with signs heart failure (SHR- F) or without evidence of failure (SHR-NF), and from age-matched normotensive Wistar-Kyoto (WKY) rats. Compared to WKY, SHR-NF rats exhibited LV (2.2-fold), and RV (1.5-fold) hypertrophy, while SHR-F rats were characterized by comparable LV hypertrophy (2.1-fold) and augmented RV hypertrophy (2.4-fold; all p,0.01). In SHR-F hearts the level of alpha-myosin heavy chain (MHC) mRNA was decreased in both ventricles to 1/3 and 1/5 of the SHR-NF and WKY values, respectively (both p less than 0.01). Levels of beta-MHC, actin, and myosin light chains did not differ among the 3 groups in the LV. Levels of atrial natriuretic factor (ANF) mRNA were elevated 3-fold in the LV of SHR-NF rats (p less than -0.05), but were not increased in the RV of SHR-NF compared to WKY rats. During the transition to failure, ANF mRNA levels increased an additional 1.6-fold in the LV, and were incremented 4.7-fold in the RV (both p less than -0.05). The levels of fibronectin (FN), pro-alpha1(I) and pro-alpha1(III) collagen (CN) mRNAs were not elevated in either ventricle of the SHR-NF group, but were 4-5-fold higher in both ventricles of SHR-F rats (all p less than 0.05). Transforming growth factor-beta1 (TGF-beta1) mRNA abundance was not elevated in ventricles of SHR-NF rats but increased 1.3-fold in the LV and 2-fold in the RV during the transition to heart failure (both p less than 0.05). The decrease in alpha-MHC mRNA levels represents a pretranslational basis for the slowed contraction observed in cardiac muscle from failing hearts. The increase in FN and CN mRNA levels suggests that the observed increase in myocardial fibrosis in failing hearts is regulated at the level of gene expression. The increase in abundance of TGF-beta1 mRNA in conjunction with the upregulation of FN and CN genes suggests that activation of TGF-beta1 gene expression may be a mechanism initiating interstitial fibrosis during the transition from stable, compensated hypertrophy to overt heart failure.